Increase of the target inhibition effects on FLT3 based on the glycosylation and cellular localization status

2011 Fiscal Year Final Research Report

• Project/Area Number: 21591198
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Hematology
• Research Institution: Nagoya University
• Principal Investigator: KIYOI Hitoshi 名古屋大学, 大学院・医学系研究科, 准教授 (90314004)
• Project Period (FY): 2009 – 2011
• Keywords: FLT3 / チロシンキナーゼ / 糖鎖修飾 / 阻害剤 / 細胞内局在 / 併用療法 / 白血病

Research Abstract

We identified that the inhibition of glycosylation machinery reduced the cell surface expression of wild type FLT3 and induced cell death through the inhibition of activated STATs in wild type FLT3-expressing cells, but not in mutant FLT3-expressing cells. We demonstrated that the glycosylation is essential for auto-phosphorylation via FL-stimulation in wild type FLT3, and that mutant FLT3 is auto-phosphorylated within the cytoplasm before the glycosylation resulting in the cell proliferation via STATs phosphorylations.

Research Products

• [Journal Article] Using peripheral blood circulating DNA stodetect CpG global methylation status and genetic mutations in patients with myelo dysplastic syndrome (2012)
  • Author(s): Iriyama C, Tomita A, Hoshino H, Shirahata M, Furukawa-Hibi Y, Yamada K, Kiyoi H, Naoe T.
  • Journal Title: Biochem Biophys Res Commun
  • Peer Reviewed
• [Journal Article] Long-term outcome of imatinib therapy, with assessment of its dosage and blood levels, for chronic myelogenous leukemia (2012)
  • Author(s): Ohnishi K, Nakaseko C, Takeuchi J, Fujisawa S, Nagai T, Yamazaki H, Tauchi T, Imai K, Mori N, Yagasaki F, Maeda Y, Usui N, Miyazaki Y, Miyamura K, Kiyoi H, Ohtake S, Naoe T.
  • Journal Title: Cancer Sci Volume: (in press)
  • Peer Reviewed
• [Journal Article] Y654 ofβ-catenin is essential for FLT3/ITD-related tyrosine phosphorylation and nuclear localization ofβ-catenin Eur J Haematol (2012)
  • Author(s): Kajiguchi T, Katsumi A, Tanizaki R, Kiyoi H, Naoe T.
  • Volume: (in press)
  • Peer Reviewed
• [Journal Article] Molecular lesions in childhood and adult acute megakaryoblastic leukaemia (2012)
  • Author(s): Hama A, Muramatsu H, Makishima H, Sugimoto Y, Szpurka H, Jasek M, OKeefe C, Takahashi Y, Sakaguchi H, Doisaki S, Shimada A, Watanabe N, Kato K, Kiyoi H, Naoe T, Kojima S, Maciejewski JP.
  • Journal Title: Br J Haematol Volume: 156 Pages: 316-325
  • Peer Reviewed
• [Journal Article] Missense mutations in PML-RARA are critical for the lack of responsiveness to arsenic trioxide treatment (2011)
  • Author(s): Goto E, Tomita A, Hayakawa F, Atsumi A, Kiyoi H, Naoe T.
  • Journal Title: Blood Volume: 118 Pages: 1600-1609
  • Peer Reviewed
• [Journal Article] Japan Adult Leukemia Study Group. Phase Itrial of gemtuzumab ozogamicin in intensive combination chemotherapy for relapsed or refractory adult acute myeloid leukemia(AML): Japan Adult Leukemia Study Group(JALSG)-AML206 study (2011)
  • Author(s): Usui N, Takeshita A, Nakaseko C, Dobashi N, Fujita H, Kiyoi H, Kobayashi Y, Sakura T, Yahagi Y, Shigeno K, Ohwada C, Miyazaki Y, Ohtake S, Miyawaki S, Naoe T, Ohnishi K.
  • Journal Title: Cancer Sci Volume: 102 Pages: 1358-1365
  • Peer Reviewed
• [Journal Article] Anovel insertion mutation of K294RGG within BCR-ABL kinase domain confers imatinib-resistance : sequential analysis of the clonal evolution in a patient with chronic myeloid leukemia in blast crisis (2011)
  • Author(s): Sakai K, Ishikawa Y, Mori Y, Kobayashi M, Iriyama C, Ozawa Y, Suzuki T, Minami Y, Ishikawa K, Kaneda N, Naoe T, Kiyoi H.
  • Journal Title: Int J Hematol Volume: 93 Pages: 237-242
  • Peer Reviewed
• [Journal Article] Prevalence and clinical characteristics of N-terminally truncated WT1 expression in acute myeloid leukemia (2011)
  • Author(s): Ishikawa Y, Kiyoi H, Naoe T.
  • Journal Title: Leuk Res Volume: 35 Pages: 685-688
  • Peer Reviewed
• [Journal Article] A randomized comparison of four courses of standard-dose multiagent chemotherapy versus three courses of high-dose cytarabine alone in post-remission therapy for acute myeloid leukemia in adults : the JALSG AML201 study (2011)
  • Author(s): Miyawaki S, Ohtake S, Fujisawa S, Kiyoi H, Shinagawa K, Usui N, Sakura T, Miyamura K, Nakaseko C, Miyazaki Y, Fujieda A, Nagai T, Yamane T, Taniwaki M, Takahashi M, Yagasaki F, Kimura Y, Asou N, Sakamaki H, Handa H, Honda S, Ohnishi K, Naoe T, Ohno R.
  • Journal Title: Blood Volume: 117 Pages: 2366-2372
  • Peer Reviewed
• [Journal Article] Randomized study of induction therapy comparing standard-dose idarubicin with high-dose daunorubicin in adult patients with previously untreated acute myeloid leukemia : JALSG AML201 Study (2011)
  • Author(s): Ohtake S, Miyawaki S, Fujita H, Kiyoi H, Shinagawa K, Usui N, Okumura H, Miyamura K, Nakaseko C, Miyazaki Y, Fujieda A, Nagai T, Yamane T, Taniwaki M, Takahashi M, Yagasaki F, Kimura Y, Asou N, Sakamaki H, Handa H, Honda S, Ohnishi K, Naoe T, Ohno R.
  • Journal Title: Blood Volume: 117 Pages: 2358-2365
  • Peer Reviewed
• [Journal Article] FLT3/ITD regulate sleukaemia cell adhesion throughα4β1integrin and Pyk2 signaling (2011)
  • Author(s): Katsumi A, Kiyoi H, Abe A, Tanizaki R, Iwasaki T, Kobayashi M, Matsushita T, Senga T, Kohno T, Kojima T, Kaibuchi K, Hamaguchi M, Naoe T.
  • Journal Title: Eur J Haematol Volume: 86 Pages: 191-198
  • Peer Reviewed
• [Journal Article] Selective KIT inhibitor KI-328 and HSP90 inhibitor show different potency against the type of KIT mutations recurrently identified in acute myeloid leukemia (2010)
  • Author(s): Tsujimura A, Kiyoi H, Shiotsu Y, Ishikawa Y, Mori Y, Ishida H, Toki T, Ito E, Naoe T.
  • Journal Title: Int J Hematol Volume: 92 Pages: 624-633
  • Peer Reviewed
• [Journal Article] Trough plasma concentration of imatinib reflects BCR-ABL kinase in hibitory activity and clinical response in chronic-phase chronic myeloid leukemia : a report from the BINGO study (2010)
  • Author(s): Ishikawa Y, Kiyoi H, Watanabe K, Miyamura K, Nakano Y, Kitamura K, Kohno A, Sugiura I, Yokozawa T, Hanamura A, Yamamoto K, Iida H, Emi N, Suzuki R, Ohnishi K, Naoe T.
  • Journal Title: Cancer Sci Volume: 101 Pages: 2186-2192
  • Peer Reviewed
• [Journal Article] Array-based genomic resequencing of human leukemia (2010)
  • Author(s): Yamashita Y, Yuan J, Suetake I, Suzuki H, Ishikawa Y, Choi YL, Ueno T, Soda M, Hamada T, Haruta H, Takada S, Miyazaki Y, Kiyoi H, Ito E, Naoe T, Tomonaga M, Toyota M, Tajima S, Iwama A, Mano H.
  • Journal Title: Oncogene Volume: 29 Pages: 3723-3731
  • Peer Reviewed
• [Journal Article] Phase I study of KW-0761, a defucosylated humanized anti-CCR4 antibody, in relapsed patients with adult T-cell leukemia-lymphoma and peripheral T-cell lymphoma (2010)
  • Author(s): Yamamoto K, Utsunomiya A, Tobinai K, Tsukasaki K, Uike N, Uozumi K, Yamaguchi K, Yamada Y, Hanada S, Tamura K, Nakamura S, Inagaki H, Ohshima K, Kiyoi H, Ishida T, Matsushima K, Akinaga S, Ogura M, Tomonaga M, Ueda R.
  • Journal Title: J Clin Oncol Volume: 28 Pages: 1591-8
  • Peer Reviewed
• [Journal Article] Irrespective of CD34 expression, lineage-committed cell fraction reconstitutes and re-establishes transformed Philadelphia chromosome-positive leukemia in NOD/SCID/IL-2Rgammac mice (2010)
  • Author(s): Tanizaki R, Nomura Y, Miyata Y, Minami Y, Abe A, Hanamura A, Sawa M, Murata M, Kiyoi H, Matsushita T, Naoe T.
  • Journal Title: Cancer Sci Volume: 101 Pages: 631-638
  • Peer Reviewed
• [Journal Article] Escape mechanisms from antibody therapy to lymphoma cells : down regulation of CD 20 mRNA by recruitment of the HDAC complex and not by DNA methylation (2009)
  • Author(s): Sugimoto T, Tomita A, Hiraga J, Shimada K, Kiyoi H, Kinoshita T, Naoe T.
  • Journal Title: Biochem Biophys Res Commun Volume: 390 Pages: 48-53
  • Peer Reviewed
• [Journal Article] KW-2449, a novel multi-kinase in hibit or, suppresses the growth of leukemia cells with FLT3 mutations or T315I-mutatedBCR/ABL translocation (2009)
  • Author(s): Shiotsu Y, Kiyoi H, Ishikawa Y, Tanizaki R, Shimizu M, Umehara H, Ishii K, Mori Y, Ozeki K, Minami Y, Abe A, Maeda H, Akiyama T, Kanda Y, Sato Y, Akinaga S, Naoe T.
  • Journal Title: Blood Volume: 114 Pages: 1607-1617
  • Peer Reviewed
• [Journal Article] Comprehensive analysis of cooperative gene mutations between class I and class II in de novo acute myeloid leukemia (2009)
  • Author(s): Ishikawa Y, Kiyoi H, Tsujimura A, Miyawaki S, Miyazaki Y, Kuriyama K, Tomonaga M, Naoe T.
  • Journal Title: Eur J Haematol Volume: 83 Pages: 90-98
  • Peer Reviewed
• [Journal Article] Down-regulation of CD20 expression in B-cell lymphoma cells after treatment with rituximab-containing combination chemo the rapies : its prevalence and clinical significance (2009)
  • Author(s): Hiraga J, Tomita A, Sugimoto T, Shimada K, Ito M, Nakamura S, Kiyoi H, Kinoshita T, Naoe T.
  • Journal Title: Blood Volume: 113 Pages: 4885-4893
  • Peer Reviewed
• [Presentation] 急性骨髄性白血病における分子病態に基づく予後層別化と個別化治療 (2011)
  • Author(s): 清井仁
  • Organizer: 第49回日本癌治療学会総会(招待講演)
  • Place of Presentation: 名古屋国際会議場(愛知県)
  • Year and Date: 2011-10-27
• [Presentation] AML病態研究の進展と最近の治療エビデンス (2011)
  • Author(s): 清井仁
  • Organizer: 第73回日本血液学会学術総会(招待講演)
  • Place of Presentation: 名古屋国際会議場(愛知県)
  • Year and Date: 2011-10-16
• [Presentation] 急性白血病の分子標的治療 (2010)
  • Author(s): 清井仁
  • Organizer: 第48回日本癌治療学会(招待講演)
  • Place of Presentation: 京都国際会議場(京都府)
  • Year and Date: 2010-10-30
• [Presentation] Prognostic classification and the development of individual therapy based on the genetic alterations in AML (2010)
  • Author(s): Hitoshi Kiyoi
  • Organizer: 第69回日本癌学会総会
  • Place of Presentation: 大阪国際会議場(大阪府)
  • Year and Date: 2010-09-22